Genetic profile of advanced thyroid cancers in relation to distant metastasis

in Endocrine-Related Cancer
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  • 1 Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Republic of Korea
  • | 2 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Republic of Korea

Correspondence should be addressed to M J Jeon or W G Kim: mj080332@gmail.com or wongukim@amc.seoul.kr
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Major clinical challenges exist with differentiated thyroid cancers with distant metastases or rare but aggressive types, such as poorly differentiated thyroid carcinomas and anaplastic thyroid carcinomas. The precise characterization of the mutational profile in these advanced thyroid cancers is crucial. Samples were collected from primary tumors and distant metastases of 64 patients with distant metastases from differentiated thyroid cancer, poorly differentiated thyroid carcinoma, or anaplastic thyroid carcinoma. Targeted next-generation sequencing was performed with 50 known thyroid-cancer-related genes. Of the 82 tissues, 63 were from primary tumors and 19 from distant metastases. The most prevalent mutation observed from the primary tumors was TERT promoter mutation (56%), followed by BRAF (41%) and RAS (24%) mutations. TP3 was altered by 11%. Mutations in histone methyltransferases, SWI/SNF subunit–related genes, and PI3K/AKT/mTOR pathway-related genes were present in 42%, 12%, and 22%, respectively. When the mutational status was analyzed in 15 matched pairs of thyroid tumors and their matched distant metastases and one pair of distant metastases with two distinct sites, the concordance was high. A similar frequency of mutations in TERT promoter (58%) and BRAF (42%) as well as histone methyltransferases (37%), SWI/SNF subunits (10%), and PI3K/AKT/mTOR pathway (26%) were noted. The same main, early and late mutations were practically always present in individual primary tumor–metastasis pairs. Enrichment of TERT promoter, BRAF, and RAS mutations were detected in highly advanced thyroid cancers with distant metastasis. The genetic profiles of primary thyroid tumors and their corresponding distant metastases showed a high concordance.

Abstract

Major clinical challenges exist with differentiated thyroid cancers with distant metastases or rare but aggressive types, such as poorly differentiated thyroid carcinomas and anaplastic thyroid carcinomas. The precise characterization of the mutational profile in these advanced thyroid cancers is crucial. Samples were collected from primary tumors and distant metastases of 64 patients with distant metastases from differentiated thyroid cancer, poorly differentiated thyroid carcinoma, or anaplastic thyroid carcinoma. Targeted next-generation sequencing was performed with 50 known thyroid-cancer-related genes. Of the 82 tissues, 63 were from primary tumors and 19 from distant metastases. The most prevalent mutation observed from the primary tumors was TERT promoter mutation (56%), followed by BRAF (41%) and RAS (24%) mutations. TP3 was altered by 11%. Mutations in histone methyltransferases, SWI/SNF subunit–related genes, and PI3K/AKT/mTOR pathway-related genes were present in 42%, 12%, and 22%, respectively. When the mutational status was analyzed in 15 matched pairs of thyroid tumors and their matched distant metastases and one pair of distant metastases with two distinct sites, the concordance was high. A similar frequency of mutations in TERT promoter (58%) and BRAF (42%) as well as histone methyltransferases (37%), SWI/SNF subunits (10%), and PI3K/AKT/mTOR pathway (26%) were noted. The same main, early and late mutations were practically always present in individual primary tumor–metastasis pairs. Enrichment of TERT promoter, BRAF, and RAS mutations were detected in highly advanced thyroid cancers with distant metastasis. The genetic profiles of primary thyroid tumors and their corresponding distant metastases showed a high concordance.

Introduction

Investigation of the genetic profiles of thyroid cancers and their association with clinical behavior has made remarkable progress over the past years. Point mutations in BRAF are the representative somatic mutations for differentiated thyroid carcinomas (DTCs), of which the V600E mutation is the most prevalent (Tavares et al. 2016). This mutation is associated with aggressive clinical features, such as larger tumor size, more frequent extrathyroidal extension, higher rate of lymph node metastases, and increased cancer-related mortality (Kim et al. 2012, Li et al. 2012, Xing et al. 2013). Genetic alterations involving RAS-family genes comprise another distinct feature of DTCs (Nikiforov 2008, Prior et al. 2012). RAS mutations are suggested to play an important role in an early event in follicular thyroid carcinogenesis (Namba et al. 1990), and they are also associated with high-risk features and unfavorable clinical outcomes (Garcia-Rostan et al. 2003, Fukahori et al. 2012, Jang et al. 2014). Relevant to aggressive clinical features, mutations in the telomerase reverse transcriptase (TERT) promoter are an essential hallmark in thyroid cancers with clinically aggressive features and advanced disease (Landa et al. 2013, 2016, Liu et al. 2013). Notably, BRAF and TERT promoter mutational statuses have been incorporated as one of the criteria for risk stratification system in the American Thyroid Association guidelines (Balmelli et al. 2018).

Despite marked progress in the comprehensive characterization of genomic landscape of thyroid cancers, most investigations have focused on DTCs. For example, The Cancer Genome Atlas (TCGA) project only included the papillary thyroid carcinomas (PTCs) to develop a homogeneous cohort (Cancer Genome Atlas Research Network 2014). Limited data exist regarding the mutational profile in advanced thyroid cancers, such as poorly differentiated thyroid carcinomas (PDTCs), anaplastic thyroid carcinomas (ATCs), and DTCs with aggressive features such as distant metastases. The most extensive series of gene-targeted sequencing of PDTC and ATC to date have been reported by Landa et al. with extensive genetic characterization of these two subtypes by evaluating the mutational status according to various functional groups (Landa et al. 2016). A recent study has also investigated the genetic profiles, including evaluations based on functional groups, of 57 fetal cases of non-ATCs, which include 53% of patients with distant metastasis (Ibrahimpasic et al. 2017). Since then, to the best of our knowledge, research has not been performed using a similar approach regarding these aggressive forms of thyroid cancer, especially regarding cancers with distant metastasis, and previous findings require validation. Furthermore, distant metastasis is one of the most potent indicators of poor clinical outcomes (Haugen et al. 2016), which occurs in approximately 10% of the the patients with indolently regarded DTCs resulting in severe deterioration of survival (Durante et al. 2006, Vaisman et al. 2015). As significant clinical challenges are present with these advanced thyroid cancers, investigation of the mutational profile in these tumors is especially crucial. In this study, we defined advanced thyroid cancers as follicular-cell-derived thyroid cancers with distant metastases (DTCs, PDTCs, and ATCs) and performed targeted next-generation sequencing (NGS) for identifying the mutational status and functional groups of somatic mutations in these advanced thyroid cancers. Furthermore, in patients with whom distant metastatic tissue was available, targeted NGS was performed and was compared with the genetic profile of the corresponding primary thyroid cancer.

Materials and methods

Patients and tissue samples

Eighty-two tissue samples from primary thyroid tumors and distant metastases were collected from 64 patients with follicular-cell-derived thyroid cancers (DTC, PDTC, or ATC) with distant metastases at Asan Medical Center, Seoul, Korea. The tumors were collected between 1994 and 2017. One experienced endocrinology pathologist (D E S) reviewed all specimens. We obtained informed consent from each patient. The Institutional Review Board of the Asan Medical Center approved all data collection and subsequent analyses.

DNA extraction and targeted NGS

Targeted NGS was performed for a total of 50 genes. These 50 genes, considered to be relatively frequent mutations in thyroid cancers, were selected after a literature review (Cancer Genome Atlas Research Network 2014, Ibrahimpasic et al. 2017) (Supplementary Table 1, see section on supplementary materials given at the end of this article). The chosen study pathologist appropriated tissue blocks for the isolation of DNA from formalin-fixed, paraffin-embedded samples. Genomic DNA was extracted from 2–5-µm thick sections from each specimen. The quantification and qualification of DNA was performed using PicoGreen and Nanodrop (Thermofisher Scientific) following the manufacturers’ protocols. The Agilent SureSelect Target Enrichment protocol (version B.3, Agilent Technologies) was used to generate standard exome capture libraries. Briefly, 1 µg of DNA was fragmented by adaptive focused acoustic technology (Covaris Inc., Woburn, MA, USA). A DNA library was prepared by sequential reactions of end repair, A-tailing, and ligation with Agilent adapters. We hybridized 250 ng of the DNA library with SureSelect exome capture baits for exome capture. After amplification of the captured DNA, the final purified product was quantified according to the qPCR Quantification Protocol Guide (Illumina, San Diego, CA, USA) and qualified using TapeStation DNA ScreenTape (Agilent Technologies). Lastly, we used a HiSeq™ 2500 platform (Illumina) for sequencing.

Analysis process

First, the sequenced reads were mapped onto the human reference genome (NCBI build 37) with the Burrows–Wheeler Aligner (version 0.7.12). The Picard-tools (version 1.130) were used to remove PCR duplicates. De-duplicated reads were locally realigned with the Genome Analysis Toolkit (GATK version 3.4.0). Variant genotyping for each sample was performed with Haplotype Caller of GATK, and these variants were annotated by SnpEff (version 4.1g), the dbSNP (version 142), the 1000 genome project (phase 3), ClinVar, and ESP6500. Common germline variants or false-positive variants were manually filtered out. Frequently altered known driver mutations were arranged in a common order. Other genes were categorized into three functional groups according to previous studies (Landa et al. 2016, Ibrahimpasic et al. 2017): histone methyltransferases (HMTs), genes encoding SWI/SNF chromatin remodeling complex, and the members of PI3K/AKT/mTOR pathway. The mean depth of target lesions of each sample ranged from 155.6 to 2705.4.

Results

Tissue samples and clinical data

A total of 82 tissues were available for genetic analyses from 64 patients as follows: 63 tissues of primary thyroid tumor and 19 distant metastatic tissues (Table 1). The mutational profile was also analyzed in 15 matched pairs with both thyroid tumors and corresponding distant metastases and one pair of two distinct sites of distant metastases from whom primary thyroid tissue was not available.

Table 1

Number of patients and tissue samples included in the study.

n
Number of tumors included in the study82
 Total number of primary thyroid tumor tissues analyzed63
 Total number of distant metastases tissues analyzed19
 Number of matched pairs of a thyroid tumor and distant metastases15
 Number of matched pairs of distinct distant metastases sites 1

Table 2 summarizes the baseline characteristics of 64 patients with advanced thyroid carcinomas in this study. The mean age was 56 years (s.d. ± 16), and 48.4% of the patients were female. The median primary tumor size was 3.0 cm (Interquartile range (IQR) 2.0–5.0) with presence of cervical lymph node metastases in 75% of the patients. Synchronous distant metastases were found in 59.4% of the patients and metachronous distant metastases were found in 40.6%. The lungs were the most common metastatic site (73.4%), followed by bones (42.2%) and the brain (6.2%).

Table 2

Baseline characteristics.

CharacteristicsValue (n = 64)
Pathology
 PTC32 (50%)
 FTC11 (17.2%)
 PDTC5 (7.8%)
 ATC16 (25%)
Age (years)56 ± 16
 ≥55 years34 (53.1%)
Gender (female)31 (48.4%)
Primary tumor size (cm)3.0 (2.0–5.0)
Extrathyroidal extension
 Microscopic31 (48.4%)
 Gross14 (21.9%)
Multifocality (yes) 24 (37.5%)
Lymph node metastases (yes)48 (75%)
Distant metastases
 Synchronous38 (59.4%)
 Metachronous26 (40.6%)
Metastatic sites
 Lung47 (73.4%)
 Bone27 (42.2%)
 Brain4 (6.2%)
 Others (liver, adrenal gland, pancreas)5 (7.8%)
AJCC TNM eighth stage at initial diagnosis
 I12 (18.8%)
 II22 (34.4%)
 III1 (1.6%)
 IV29 (45.3%)

Somatic mutations in the primary tumor of thyroid cancers with distant metastasis

Targeted NGS of 63 primary thyroid tumors detected a median of three (IQR 2–4) somatic mutations in advanced thyroid carcinomas (Fig. 1A). Among the identified variants, TERT promoter mutations showed the highest prevalence (56%), followed by mutations in BRAF V600E (41%) and RAS (24%).

Figure 1
Figure 1

Mutations in 63 primary thyroid tumors. (A) Numbers of mutations, (B) driver genes, (C) TERT promoter, (D) tumor suppressor genes, (E) key pathways and functional groups, and (F) other genes. Sample numbers in red letters indicate samples with available distant metastases tissues.

Citation: Endocrine-Related Cancer 27, 5; 10.1530/ERC-19-0452

Mutations in drivers and other relevant genes

BRAF V600E mutation was present in 26 samples (41%) as follows: 19 of PTCs, 1 of PDTC, and 6 of ATCs (Fig. 1B). In patients without BRAF V600E mutation, NRAS, KRAS, and HRAS variants were found in 11 (17%), 3 (5%), and 1 (2%) samples, respectively. Virtually all RAS mutations were accompanied by TERT promoter mutations. Other driver mutations observed in advanced thyroid carcinomas were ALK (6%), NF1 (6%), and APC (5%).

Mutation in TERT promoter

The TERT promoter mutation showed the highest prevalence of 56% among all mutations detected in this study (Fig. 1C). Specifically, 45% (14/31) of PTCs, 82% (9/11) of follicular thyroid carcinomas (FTCs), 20% (1/5) of PDTCs, and 59% (11/16) of ATCs harbored a TERT promoter mutation. Together, C228T (27/35) was the most common mutation, followed by C250T (5/35), C228A (2/35), and C242T (1/35).

Mutations in tumor suppressor genes

ZFHX3, which has been reported to function as a tumor suppressor in several cancers, was mutated in eight samples (13%) (Fig. 1D). The second-most common mutation in tumor suppressor genes was a TP53 mutation (11%, 7/63), which is considered as a hallmark of advanced thyroid carcinomas. Particularly high TP53 mutation burden was prevalent in ATCs (six out of seven). Other mutations were found in CHEK2 (6%) and NF2 (2%).

Mutations in key pathways and functional groups

Mutations in HMTs, KMT2C, KMT2D, and KMT2A were present in 42% of advanced thyroid carcinomas (Fig. 1E). Genes encoding SWI/SNF chromatin remodeling complex were altered in 12%: 5% in ARID1A, 5% in ARID1B, and 2% in ARID2. Mutations of genes encoding the members of PI3K/AKT/mTOR pathway were observed in 14 samples (22%), including PIK3CA, PIK3C2G, AKT1, TSC2, and MTOR. MSH2, a member of the DNA MMR pathway, was found in 6% of advanced thyroid carcinomas. Alterations in genes, other than in the previously mentioned categories, are shown in Fig. 1F.

Mutational profile in primary tumor and distant metastases in matched pairs

We performed targeted NGS of 15 matched pairs of thyroid tumors and distant metastases and one pair of two distinct sites of distant metastases. Median of three (IQR 2–4) somatic mutations was detected in total 34 samples and the same median of three (IQR 2–4) mutations for distant metastases only (Fig. 2A). The TERT promoter mutation was the most prevalent with 53% of the total samples and 58% (11/19) of distant metastases (Fig. 2C). BRAF V600E mutation was the second-most commonly detected mutation and was present in 13 samples (38%) (Fig. 2B). Mutation in RAS was prevalent in 13 samples (39%) with KRAS in seven, NRAS in four, and HRAS in two samples. It was mutated all in pairs and was mutually exclusive with BRAF V600E mutation (Fig. 2B). Other frequent mutations found in these matched pair analyses were mutations in NF1 (18%) in driver mutations, ZFHX3 (18%) in tumor suppressor genes, KMT2C (26%) in HMTs, and others such as TG (21%) and BDP1 (18%). When comparing between the individual pairs of primary tumor tissue and its matched metastatic tissue with the same sample number in Fig. 2, the same mutations in specific genes were almost always present, regardless of the type of metastasis (synchronous or metachronous). There were no particularly frequent mutations observed in distant metastases compared with those observed in thyroid tumors.

Figure 2
Figure 2

Mutations in matched pairs. (A) Numbers of mutations, (B) driver genes, (C) TERT promoter, (D) ZFHX3, (E) key pathways and functional groups, and (F) other genes. Pairs of the primary thyroid tumor and matched distant metastasis are arranged from left to right. Sample numbers in blue indicate samples with synchronous metastases, while those in red indicate samples with metachronous metastases. Sample numbers with quotation marks indicate the distant metastases samples.

Citation: Endocrine-Related Cancer 27, 5; 10.1530/ERC-19-0452

Figure 3 shows the comparison of mutation burdens between primary tumors (63 samples) and distant metastases (19 samples), including the two-most commonly observed mutations of TERT promoter and BRAF. All two major mutations showed similar frequency between primary tumors and distant metastases: TERT promoter mutation in 56% of primary tumors and 58% (11/19) of distant metastases (Fig. 3A) and BRAF V600E mutation in 41% of primary tumors and 42% (8/19) of distant metastases (Fig. 3B). Moreover, mutations in HMTs, SWI/SNF subunits, and PI3K/AKT/mTOR were observed in similar frequencies between the two groups (Fig. 3C, D and E). RAS mutation was observed in 24% of primary tumors but in 37% (7/19) of distant metastases, which may be attributable to the selection bias, as primary tumors of these distant metastases samples also showed prevalent RAS mutation (33%).

Figure 3
Figure 3

Frequency of mutations in (A) TERT promoter, (B) BRAF, (C) histone methyltransferases, (D) SWI/SNF subunits, and (E) PI3K/AKT/mTOR pathway in primary tumors and distant metastases. Mut, mutated; wt, wild type.

Citation: Endocrine-Related Cancer 27, 5; 10.1530/ERC-19-0452

Genetic profiles on the basis of the RAI avidity of samples with distant metastases were also evaluated (Fig. 4A). We found that samples with RAI non-avidity harbored more frequent mutations in the TERT promoter, BRAF, HMTs, and the PIK3/AKT/mTOR pathway compared with samples with RAI avidity.

Figure 4
Figure 4

Mutational comparison between (A) radioactive iodine-avid and non-avid samples and (B) non-ATCs and ATCs.

Citation: Endocrine-Related Cancer 27, 5; 10.1530/ERC-19-0452

Mutational comparison between non-ATCs and ATCs

Figure 4B compares the mutational rate of some of the commonly observed genes and functional groups between non-ATCs and ATCs. Alterations in driver mutation, such as BRAF (42% vs 37%), HMTs (38% vs 50%), or the PI3K/AKT/mTOR pathway (23% vs 19%), were comparable between the two groups. However, ATCs harbored 69% of TERT promoter mutation, whereas non-ATCs showed a less mutational rate of 50%. Marked enrichment of TP3 (2% vs 37%) mutation was also observed in ATCs in comparison with the non-ATCs. RAS mutation was more prevalent in non-ATCs (27%) than in ATCs (12%).

Discussion

DTCs account for more than 90% of thyroid cancers (Burns & Zeiger 2010), and they are among the most curable cancers with a 10-year survival rate of 85% to 95% (Hundahl et al. 1998, Kim et al. 2014, Han et al. 2018). However, approximately 10% of these patients with DTC develop distant metastases, and the overall 10-year survival rate after the detection of distant metastases decreases to about 40% (Schlumberger 1998). There are also rare types of thyroid cancers, including PDTCs, which account for approximately 1–15% of thyroid cancers in which disease-specific deaths mostly occur due to distant metastases (Ibrahimpasic et al. 2014). Also, ATCs compromised only 1–2% of thyroid cancers, but they contribute to up to 50% of the mortality (Nagaiah et al. 2011). A substantial portion of DTCs with distant metastases, PDTCs and ATCs, are refractory to radioactive iodine. Significant clinical decisions are impacted by DTCs and PDTCs with distant metastases and ATCs. In this aspect, and in the era of precision medicine and targeted therapies for cancer treatment, precise genetic profiles in these advanced thyroid cancers are indispensable.

In the present study, we performed targeted NGS for identifying the mutations in advanced thyroid cancers and for evaluating the concordance between the mutational status of distant metastasis and its matched primary tumor. Our results show that the TERT promoter (56%), BRAF (41%), and RAS (24%) mutations are the three most prevalent in advanced thyroid carcinomas. When compared with matched primary thyroid tumors, the genetic profile of distant metastasis showed a similar pattern, with TERT promotor (58%) and BRAF (42%) mutations being the most common alterations. We also characterized the mutational status of advanced thyroid cancers stratified by the functional groups, a similar approach used in previous studies (Landa et al. 2016, Ibrahimpasic et al. 2017). We identified similar rates of gene mutations in HMTs, genes encoding SWI/SNP chromatin remodeling complex, and the members of PI3K/AKT/mTOR pathway between primary tumors and distant metastases. More importantly, the same main, early and late mutations were practically always present in individual primary tumor–metastasis pairs, indicating that the genetic profile of distant metastasis can be inferred by analyzing a resected primary tumor. No particularly prevalent mutation was noted in distant metastasis samples. In addition, non-ATCs and ATCs harbored similar rates of mutation in BRAF, HMTs, and the PI3K/AKT/mTOR pathway. However, a higher mutational burden was observed in the TERT promoter gene and TP3 in ATCs compared with non-ATCs.

The TERT promoter mutation is a well-known indicator of high-risk thyroid cancers (Landa et al. 2013, 2016, Liu et al. 2013). Accordingly, this mutation was most commonly identified in thyroid tumors (56%) and distant metastases (58%) in our dataset, contrasting wtih 9.4% in PTC samples from TGCA study. Researchers have observed the association between the TERT promoter mutation and distant metastases (Melo et al. 2014, 2017, Qasem et al. 2015, Liu & Xing 2016). This association may explain the high mutation burden of TERT promoter in our research, as all patients had distant metastases. The next most common mutation was the BRAF mutation, which has gained considerable data regarding its role in aggressive behavior of thyroid cancers from previous literature (Kim et al. 2012, Li et al. 2012, Xing et al. 2013). However, its association with increased risk of distant metastases is unclear (Liu et al. 2016, Zhang et al. 2016). In our study, 41% of primary thyroid tumors and 42% of distant metastases harbored BRAF mutation and most of them were tissues from patients with PTC (73.1%, 19 out of 26).

Along with the critical mutations in advanced thyroid cancers, another vital issue to be addressed from our study is the similar mutational status of these key mutations between primary thyroid tumors and their matched distant metastases. Not much is known regarding the relationship between primary tumors and the corresponding metastases. Our group recently explored the mutational profile of micro-PTCs and their matched lymph node metastases and reported that genetic profile was not significantly different between the two (Jeon et al. 2019). However, this study did not include the evaluation of distant metastases, which plays a key role in the clinical outcome. A previous study by Melo et al. investigated the concordance of genetic profile between the primary tumor, corresponding lymph node, and distant metastases by focusing on three genes, which were TERT promoter, BRAF, and NRAS (Melo et al. 2017). This study reported a high concordance of the genotype of primary tumors and that of lymph node metastases but a significant difference in the frequency of TERT promoter mutation between thyroid tumors (15.9%) and distant metastases (52.4%) (Melo et al. 2017). This result does not match with the findings of our study and the difference in patient cohort may partially explain this discrepancy; patients with PTC in the cited research accounted for 88.2% (180/204) of the total patients, and only 35 of all the patients with PTC had distant metastases. There were 14 patients (6.9%) with distant metastases from FTC and seven patients (3.4%) with distant metastases from PDTCs and ATCs together. In total, 27.9% of the cited study patients had distant metastases – in contrast to 100% of distant metastases in our study with relative high portion of PDTCs (7.8%) and ATCs (25%) – and this may have lowered the frequency of TERT promoter mutation in that study. Enrichment in BRAF mutation was also observed in both primary thyroid tumor and distant metastasis in our study. The concordance of genotype between thyroid tumors and distant metastases is high. We can infer from this finding that distant metastases stem from primary thyroid tumors and may not require the acquisition of new genetic alterations. Instead, other factors, such as tumor microenvironment, may play the crucial role in the process of distant metastases. Further analyses are required to elucidate the exact mechanism underlying the process of distant metastases.

Limited data exists regarding the precise genotype of advanced thyroid carcinomas and their metastatic tissue, especially distant metastases. In this aspect, as its strength, our study explored the key mutations in a relatively homogenous cohort of patients with highly advanced thyroid carcinomas: DTCs, PDTCs, and ATCs will all distant metastases. We also investigated the genetic profile of both the primary thyroid tumors and distant metastases as a matched pair, which can provide informative data regarding the role of genetic alteration in the process of distant metastases. Nevertheless, some limitations must be addressed. First, we performed targeted sequencing with only 50 thyroid-cancer-related genes. This may have biased the association between primary thyroid tumors and distant metastases. Also, we could not test the rearrangements. Thus, we lacked data on RET or ALK rearrangements, which are frequently reported genetic alterations in thyroid cancers (Hundahl et al. 1998). Furthermore, the tissues of distant metastases were collected regardless of radioactive iodine refractoriness. Therefore, the association of BRAF or TERT promoter mutations with radioactive iodine refractoriness could not be addressed from our results, which has been raised by previous studies (Riesco-Eizaguirre et al. 2006, Romei et al. 2008, Yang et al. 2017). This study also could not provide data on the comparison between samples with and without distant metastases, since we only included advanced thyroid cancers with distant metastases. Further studies are required to overcome this research gap, as these data would be highly important clinically and biologically.

In conclusion, the TERT promoter, BRAF, and RAS mutations were the three most prevalent mutations in advanced thyroid cancers. We observed a high concordance in the genetic profile between the primary thyroid tumors and their corresponding distant metastases. Our findings suggest the limited role of additional genetic alteration in the processes associated with distant metastases. Other factors, such as the tumor microenvironment, should be investigated to further understand the underlying process of distant metastases.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/ERC-19-0452.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This study was supported by the National Research Foundation (NRF) of Korea Research Grant (NRF-2017R1D1A1B03028231 and NRF-2018R1D1A1A02085365).

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  • Landa I, Ganly I, Chan TA, Mitsutake N, Matsuse M, Ibrahimpasic T, Ghossein RA & Fagin JA 2013 Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease. Journal of Clinical Endocrinology and Metabolism 98 E1562E1566. (https://doi.org/10.1210/jc.2013-2383)

    • Search Google Scholar
    • Export Citation
  • Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, Dogan S, Ricarte-Filho JC, Krishnamoorthy GP, Xu B, et al. 2016 Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. Journal of Clinical Investigation 126 10521066. (https://doi.org/10.1172/JCI85271)

    • Search Google Scholar
    • Export Citation
  • Li C, Lee KC, Schneider EB & Zeiger MA 2012 BRAF V600E mutation and its association with clinicopathological features of papillary thyroid cancer: a meta-analysis. Journal of Clinical Endocrinology and Metabolism 97 45594570. (https://doi.org/10.1210/jc.2012-2104)

    • Search Google Scholar
    • Export Citation
  • Liu R & Xing M 2016 TERT promoter mutations in thyroid cancer. Endocrine-Related Cancer 23 R143R155. (https://doi.org/10.1530/ERC-15-0533)

    • Search Google Scholar
    • Export Citation
  • Liu X, Bishop J, Shan Y, Pai S, Liu D, Murugan AK, Sun H, El-Naggar AK & Xing M 2013 Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocrine-Related Cancer 20 603610. (https://doi.org/10.1530/ERC-13-0210)

    • Search Google Scholar
    • Export Citation
  • Liu C, Chen T & Liu Z 2016 Associations between BRAF(V600E) and prognostic factors and poor outcomes in papillary thyroid carcinoma: a meta-analysis. World Journal of Surgical Oncology 14 241. (https://doi.org/10.1186/s12957-016-0979-1)

    • Search Google Scholar
    • Export Citation
  • Melo M, da Rocha AG, Vinagre J, Batista R, Peixoto J, Tavares C, Celestino R, Almeida A, Salgado C, Eloy C, et al. 2014 TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism 99 E754E765. (https://doi.org/10.1210/jc.2013-3734)

    • Search Google Scholar
    • Export Citation
  • Melo M, Gaspar da Rocha A, Batista R, Vinagre J, Martins MJ, Costa G, Ribeiro C, Carrilho F, Leite V, Lobo C, et al. 2017 TERT, BRAF, and NRAS in primary thyroid cancer and metastatic disease. Journal of Clinical Endocrinology and Metabolism 102 18981907. (https://doi.org/10.1210/jc.2016-2785)

    • Search Google Scholar
    • Export Citation
  • Nagaiah G, Hossain A, Mooney CJ, Parmentier J & Remick SC 2011 Anaplastic thyroid cancer: a review of epidemiology, pathogenesis, and treatment. Journal of Oncology 2011 542358. (https://doi.org/10.1155/2011/542358)

    • Search Google Scholar
    • Export Citation
  • Namba H, Rubin SA & Fagin JA 1990 Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Molecular Endocrinology 4 14741479. (https://doi.org/10.1210/mend-4-10-1474)

    • Search Google Scholar
    • Export Citation
  • Nikiforov YE 2008 Thyroid carcinoma: molecular pathways and therapeutic targets. Modern Pathology 21 (Supplement 2) S37S43. (https://doi.org/10.1038/modpathol.2008.10)

    • Search Google Scholar
    • Export Citation
  • Prior IA, Lewis PD & Mattos C 2012 A comprehensive survey of Ras mutations in cancer. Cancer Research 72 24572467. (https://doi.org/10.1158/0008-5472.CAN-11-2612)

    • Search Google Scholar
    • Export Citation
  • Qasem E, Murugan AK, Al-Hindi H, Xing M, Almohanna M, Alswailem M & Alzahrani AS 2015 TERT promoter mutations in thyroid cancer: a report from a Middle Eastern population. Endocrine-Related Cancer 22 901908. (https://doi.org/10.1530/ERC-15-0396)

    • Search Google Scholar
    • Export Citation
  • Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia-Cabezas MA, Nistal M & Santisteban P 2006 The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I targeting to the membrane. Endocrine-Related Cancer 13 257269. (https://doi.org/10.1677/erc.1.01119)

    • Search Google Scholar
    • Export Citation
  • Romei C, Ciampi R, Faviana P, Agate L, Molinaro E, Bottici V, Basolo F, Miccoli P, Pacini F, Pinchera A, et al. 2008 BRAFV600E mutation, but not RET/PTC rearrangements, is correlated with a lower expression of both thyroperoxidase and sodium iodide symporter genes in papillary thyroid cancer. Endocrine-Related Cancer 15 511520. (https://doi.org/10.1677/ERC-07-0130)

    • Search Google Scholar
    • Export Citation
  • Schlumberger MJ 1998 Papillary and follicular thyroid carcinoma. New England Journal of Medicine 338 297306. (https://doi.org/10.1056/NEJM199801293380506)

    • Search Google Scholar
    • Export Citation
  • Tavares C, Melo M, Cameselle-Teijeiro JM, Soares P & Sobrinho-Simoes M 2016 ENDOCRINE TUMOURS: Genetic predictors of thyroid cancer outcome. European Journal of Endocrinology 174 R117R126. (https://doi.org/10.1530/EJE-15-0605)

    • Search Google Scholar
    • Export Citation
  • Vaisman F, Carvalho DP & Vaisman M 2015 A new appraisal of iodine refractory thyroid cancer. Endocrine-Related Cancer 22 R301R310. (https://doi.org/10.1530/ERC-15-0300)

    • Search Google Scholar
    • Export Citation
  • Xing M, Alzahrani AS, Carson KA, Viola D, Elisei R, Bendlova B, Yip L, Mian C, Vianello F, Tuttle RM, et al. 2013 Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 309 14931501. (https://doi.org/10.1001/jama.2013.3190)

    • Search Google Scholar
    • Export Citation
  • Yang X, Li J, Li X, Liang Z, Gao W, Liang J, Cheng S & Lin Y 2017 TERT promoter mutation predicts radioiodine-refractory character in distant metastatic differentiated thyroid cancer. Journal of Nuclear Medicine 58 258265. (https://doi.org/10.2967/jnumed.116.180240)

    • Search Google Scholar
    • Export Citation
  • Zhang Q, Liu SZ, Zhang Q, Guan YX, Chen QJ & Zhu QY 2016 Meta-analyses of association between BRAF(V600E) mutation and clinicopathological features of papillary thyroid carcinoma. Cellular Physiology and Biochemistry 38 763776. (https://doi.org/10.1159/000443032)

    • Search Google Scholar
    • Export Citation

 

Society for Endocrinology

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    Mutations in 63 primary thyroid tumors. (A) Numbers of mutations, (B) driver genes, (C) TERT promoter, (D) tumor suppressor genes, (E) key pathways and functional groups, and (F) other genes. Sample numbers in red letters indicate samples with available distant metastases tissues.

  • View in gallery

    Mutations in matched pairs. (A) Numbers of mutations, (B) driver genes, (C) TERT promoter, (D) ZFHX3, (E) key pathways and functional groups, and (F) other genes. Pairs of the primary thyroid tumor and matched distant metastasis are arranged from left to right. Sample numbers in blue indicate samples with synchronous metastases, while those in red indicate samples with metachronous metastases. Sample numbers with quotation marks indicate the distant metastases samples.

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    Frequency of mutations in (A) TERT promoter, (B) BRAF, (C) histone methyltransferases, (D) SWI/SNF subunits, and (E) PI3K/AKT/mTOR pathway in primary tumors and distant metastases. Mut, mutated; wt, wild type.

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    Mutational comparison between (A) radioactive iodine-avid and non-avid samples and (B) non-ATCs and ATCs.

  • Balmelli C, Railic N, Siano M, Feuerlein K, Cathomas R, Cristina V, Guthner C, Zimmermann S, Weidner S, Pless M, et al. 2018 Lenvatinib in advanced radioiodine-refractory thyroid cancer – a retrospective analysis of the Swiss lenvatinib named patient program. Journal of Cancer 9 250255. (https://doi.org/10.7150/jca.22318)

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  • Burns WR & Zeiger MA 2010 Differentiated thyroid cancer. Seminars in Oncology 37 557566. (https://doi.org/10.1053/j.seminoncol.2010.10.008)

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  • Cancer Genome Atlas Research Network 2014 Integrated genomic characterization of papillary thyroid carcinoma. Cell 159 676690. (https://doi.org/10.1016/j.cell.2014.09.050)

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  • Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, Caillou B, Ricard M, Lumbroso JD, De Vathaire F, et al. 2006 Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. Journal of Clinical Endocrinology and Metabolism 91 28922899. (https://doi.org/10.1210/jc.2005-2838)

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  • Fukahori M, Yoshida A, Hayashi H, Yoshihara M, Matsukuma S, Sakuma Y, Koizume S, Okamoto N, Kondo T, Masuda M, et al. 2012 The associations between RAS mutations and clinical characteristics in follicular thyroid tumors: new insights from a single center and a large patient cohort. Thyroid 22 683689. (https://doi.org/10.1089/thy.2011.0261)

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  • Garcia-Rostan G, Zhao H, Camp RL, Pollan M, Herrero A, Pardo J, Wu R, Carcangiu ML, Costa J & Tallini G 2003 ras mutations are associated with aggressive tumor phenotypes and poor prognosis in thyroid cancer. Journal of Clinical Oncology 21 32263235. (https://doi.org/10.1200/JCO.2003.10.130)

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  • Han JM, Bae JC, Kim HI, Kwon S, Jeon MJ, Kim WG, Kim TY, Shong YK & Kim WB 2018 Clinical outcomes of differentiated thyroid cancer patients with local recurrence or distant metastasis detected in old age. Endocrinology and Metabolism 33 459465. (https://doi.org/10.3803/EnM.2018.33.4.459)

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  • Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, et al. 2016 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on thyroid nodules and differentiated thyroid cancer. Thyroid 26 1133. (https://doi.org/10.1089/thy.2015.0020)

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  • Ibrahimpasic T, Ghossein R, Carlson DL, Nixon I, Palmer FL, Shaha AR, Patel SG, Tuttle RM, Shah JP & Ganly I 2014 Outcomes in patients with poorly differentiated thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 99 12451252. (https://doi.org/10.1210/jc.2013-3842)

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  • Ibrahimpasic T, Xu B, Landa I, Dogan S, Middha S, Seshan V, Deraje S, Carlson DL, Migliacci J, Knauf JA, et al. 2017 Genomic alterations in fatal forms of non-anaplastic thyroid cancer: identification of MED12 and RBM10 as novel thyroid cancer genes associated with tumor virulence. Clinical Cancer Research 23 59705980. (https://doi.org/10.1158/1078-0432.CCR-17-1183)

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  • Jang EK, Song DE, Sim SY, Kwon H, Choi YM, Jeon MJ, Han JM, Kim WG, Kim TY, Shong YK, et al. 2014 NRAS codon 61 mutation is associated with distant metastasis in patients with follicular thyroid carcinoma. Thyroid 24 12751281. (https://doi.org/10.1089/thy.2014.0053)

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  • Jeon MJ, Chun SM, Lee JY, Choi KW, Kim D, Kim TY, Jang SJ, Kim WB, Shong YK, Song DE, et al. 2019 Mutational profile of papillary thyroid microcarcinoma with extensive lymph node metastasis. Endocrine 64 130138. (https://doi.org/10.1007/s12020-019-01842-y)

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  • Kim TH, Park YJ, Lim JA, Ahn HY, Lee EK, Lee YJ, Kim KW, Hahn SK, Youn YK, Kim KH, et al. 2012 The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis. Cancer 118 17641773. (https://doi.org/10.1002/cncr.26500)

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  • Kim TY, Kim WG, Kim WB & Shong YK 2014 Current status and future perspectives in differentiated thyroid cancer. Endocrinology and Metabolism 29 217225. (https://doi.org/10.3803/EnM.2014.29.3.217)

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  • Landa I, Ganly I, Chan TA, Mitsutake N, Matsuse M, Ibrahimpasic T, Ghossein RA & Fagin JA 2013 Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease. Journal of Clinical Endocrinology and Metabolism 98 E1562E1566. (https://doi.org/10.1210/jc.2013-2383)

    • Search Google Scholar
    • Export Citation
  • Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, Dogan S, Ricarte-Filho JC, Krishnamoorthy GP, Xu B, et al. 2016 Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. Journal of Clinical Investigation 126 10521066. (https://doi.org/10.1172/JCI85271)

    • Search Google Scholar
    • Export Citation
  • Li C, Lee KC, Schneider EB & Zeiger MA 2012 BRAF V600E mutation and its association with clinicopathological features of papillary thyroid cancer: a meta-analysis. Journal of Clinical Endocrinology and Metabolism 97 45594570. (https://doi.org/10.1210/jc.2012-2104)

    • Search Google Scholar
    • Export Citation
  • Liu R & Xing M 2016 TERT promoter mutations in thyroid cancer. Endocrine-Related Cancer 23 R143R155. (https://doi.org/10.1530/ERC-15-0533)

    • Search Google Scholar
    • Export Citation
  • Liu X, Bishop J, Shan Y, Pai S, Liu D, Murugan AK, Sun H, El-Naggar AK & Xing M 2013 Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocrine-Related Cancer 20 603610. (https://doi.org/10.1530/ERC-13-0210)

    • Search Google Scholar
    • Export Citation
  • Liu C, Chen T & Liu Z 2016 Associations between BRAF(V600E) and prognostic factors and poor outcomes in papillary thyroid carcinoma: a meta-analysis. World Journal of Surgical Oncology 14 241. (https://doi.org/10.1186/s12957-016-0979-1)

    • Search Google Scholar
    • Export Citation
  • Melo M, da Rocha AG, Vinagre J, Batista R, Peixoto J, Tavares C, Celestino R, Almeida A, Salgado C, Eloy C, et al. 2014 TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. Journal of Clinical Endocrinology and Metabolism 99 E754E765. (https://doi.org/10.1210/jc.2013-3734)

    • Search Google Scholar
    • Export Citation
  • Melo M, Gaspar da Rocha A, Batista R, Vinagre J, Martins MJ, Costa G, Ribeiro C, Carrilho F, Leite V, Lobo C, et al. 2017 TERT, BRAF, and NRAS in primary thyroid cancer and metastatic disease. Journal of Clinical Endocrinology and Metabolism 102 18981907. (https://doi.org/10.1210/jc.2016-2785)

    • Search Google Scholar
    • Export Citation
  • Nagaiah G, Hossain A, Mooney CJ, Parmentier J & Remick SC 2011 Anaplastic thyroid cancer: a review of epidemiology, pathogenesis, and treatment. Journal of Oncology 2011 542358. (https://doi.org/10.1155/2011/542358)

    • Search Google Scholar
    • Export Citation
  • Namba H, Rubin SA & Fagin JA 1990 Point mutations of ras oncogenes are an early event in thyroid tumorigenesis. Molecular Endocrinology 4 14741479. (https://doi.org/10.1210/mend-4-10-1474)

    • Search Google Scholar
    • Export Citation
  • Nikiforov YE 2008 Thyroid carcinoma: molecular pathways and therapeutic targets. Modern Pathology 21 (Supplement 2) S37S43. (https://doi.org/10.1038/modpathol.2008.10)

    • Search Google Scholar
    • Export Citation
  • Prior IA, Lewis PD & Mattos C 2012 A comprehensive survey of Ras mutations in cancer. Cancer Research 72 24572467. (https://doi.org/10.1158/0008-5472.CAN-11-2612)

    • Search Google Scholar
    • Export Citation
  • Qasem E, Murugan AK, Al-Hindi H, Xing M, Almohanna M, Alswailem M & Alzahrani AS 2015 TERT promoter mutations in thyroid cancer: a report from a Middle Eastern population. Endocrine-Related Cancer 22 901908. (https://doi.org/10.1530/ERC-15-0396)

    • Search Google Scholar
    • Export Citation
  • Riesco-Eizaguirre G, Gutierrez-Martinez P, Garcia-Cabezas MA, Nistal M & Santisteban P 2006 The oncogene BRAF V600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I targeting to the membrane. Endocrine-Related Cancer 13 257269. (https://doi.org/10.1677/erc.1.01119)

    • Search Google Scholar
    • Export Citation
  • Romei C, Ciampi R, Faviana P, Agate L, Molinaro E, Bottici V, Basolo F, Miccoli P, Pacini F, Pinchera A, et al. 2008 BRAFV600E mutation, but not RET/PTC rearrangements, is correlated with a lower expression of both thyroperoxidase and sodium iodide symporter genes in papillary thyroid cancer. Endocrine-Related Cancer 15 511520. (https://doi.org/10.1677/ERC-07-0130)

    • Search Google Scholar
    • Export Citation
  • Schlumberger MJ 1998 Papillary and follicular thyroid carcinoma. New England Journal of Medicine 338 297306. (https://doi.org/10.1056/NEJM199801293380506)

    • Search Google Scholar
    • Export Citation
  • Tavares C, Melo M, Cameselle-Teijeiro JM, Soares P & Sobrinho-Simoes M 2016 ENDOCRINE TUMOURS: Genetic predictors of thyroid cancer outcome. European Journal of Endocrinology 174 R117R126. (https://doi.org/10.1530/EJE-15-0605)

    • Search Google Scholar
    • Export Citation
  • Vaisman F, Carvalho DP & Vaisman M 2015 A new appraisal of iodine refractory thyroid cancer. Endocrine-Related Cancer 22 R301R310. (https://doi.org/10.1530/ERC-15-0300)

    • Search Google Scholar
    • Export Citation
  • Xing M, Alzahrani AS, Carson KA, Viola D, Elisei R, Bendlova B, Yip L, Mian C, Vianello F, Tuttle RM, et al. 2013 Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 309 14931501. (https://doi.org/10.1001/jama.2013.3190)

    • Search Google Scholar
    • Export Citation
  • Yang X, Li J, Li X, Liang Z, Gao W, Liang J, Cheng S & Lin Y 2017 TERT promoter mutation predicts radioiodine-refractory character in distant metastatic differentiated thyroid cancer. Journal of Nuclear Medicine 58 258265. (https://doi.org/10.2967/jnumed.116.180240)

    • Search Google Scholar
    • Export Citation
  • Zhang Q, Liu SZ, Zhang Q, Guan YX, Chen QJ & Zhu QY 2016 Meta-analyses of association between BRAF(V600E) mutation and clinicopathological features of papillary thyroid carcinoma. Cellular Physiology and Biochemistry 38 763776. (https://doi.org/10.1159/000443032)

    • Search Google Scholar
    • Export Citation